Divergent Synthesis of Polymethoxylated 4-Aryl-2-quinolones

Article abstract of DOI:10.1021/acs.joc.6b02626

Polymethoxylated 4-aryl-2-quinolones were synthesized from the corresponding (o-aminophenyl)propiolates via Cu-catalyzed hydroarylation and subsequent deprotection/lactam formation. Selective iodination of the C3 position of the product followed by coupli

Full text of DOI:10.1021/acs.joc.6b02626

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Article
Divergent Synthesis of Polymethoxylated 4-Aryl-2-quinolones
Tsukasa Murayama, Masatoshi Shibuya, and Yoshihiko Yamamoto
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02626 • Publication Date (Web): 08 Nov 2016
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Divergent Synthesis of Polymethoxylated 4ꢀArylꢀ2ꢀquinolones
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Tsukasa Murayama, Masatoshi Shibuya, and Yoshihiko Yamamoto*
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences,
Nagoya University, Chikusa, Nagoya 464-8601, Japan
*yamamotoꢀyoshi@ps.nagoyaꢀu.ac.jp
ABSTRACT: Polymethoxylated 4ꢀarylꢀ2ꢀquinolones were synthesized from the
corresponding (oꢀaminophenyl)propiolates via Cuꢀcatalyzed hydroarylation and
subsequent deprotection/lactam cyclization. Selective iodination of the C3 position of the
product followed by coupling reactions of the resulting 3ꢀiodinated 4ꢀarylꢀ2ꢀquinolone
afforded 3ꢀsubstitutedꢀ4ꢀarylꢀ2ꢀquinolones. Moreover, the Nꢀbenzyl protecting group was
successfully replaced with other polyoxygenated benzyl groups.
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INTRODUCTION
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4ꢀPhenylꢀ2ꢀquinolone is an important nitrogenꢀcontaining heterocyclic scaffold
found in natural products and drug molecules (Figure 1).1,2 Therefore, a wide variety of
methods have been developed for the efficient construction of 4ꢀarylꢀ2ꢀquinolone core
structures.3 In this respect, the diversification of 4ꢀarylꢀ2ꢀquinolones would provide a
promising strategy for efficiently generating potent drug candidates.4 Nevertheless, such
an intriguing tactic has received less attention, and to the best of our knowledge, no
divergent synthesis of polymethoxylated analogs has been reported.5
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Figure 1. Examples of bioactive 4ꢀarylꢀ2ꢀquinolones.
Therefore, we focused on the efficient construction and diverted transformations of
a polymethoxylated quinolone core (Figure 2). This is because Tsubuki and coꢀworkers
reported that 4ꢀ(4ꢀfluorophenyl)ꢀ5,6,7ꢀtrimethoxyquinolinꢀ2(1H)ꢀone (1) is a potential
inhibitor of amyloid β fibrogenesis (Figure 1).6 Moreover, 2ꢀquinolone alkaloids with a
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dimethoxylated 2ꢀquinolone core were also isolated from Chiococca alba; however, no
biological activity was reported (Figure 1).1a The diversification of such a
polymethoxylated 4ꢀarylꢀ2ꢀquinolone may lead to the discovery of novel bioactive
compounds. To this end, we selected the C4 aryl groups, C3 substituents, and Nꢀbenzyl
groups as the diversifying points, because the reported bioactive compounds show
considerable diversities in these substituents as shown in Figure 1.
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Figure 2. Divergent synthesis of polymethoxy 4ꢀarylꢀ2ꢀquinolone.
To exemplify this strategy, it is essential to efficiently install aryl groups at the C4
position of a polymethoxylated quinolone core. Previously, we reported the modular
synthesis of 4ꢀarylꢀ2ꢀquinolones via the Cuꢀcatalyzed hydroarylation of
(oꢀaminophenyl)propiolates with arylboronates and subsequent deprotection/lactam
formation.7 This method enabled the synthesis of diverse 4ꢀarylꢀ2ꢀquinolones including a
hepatitis B virus inhibitor.2f However, a serious drawback was observed when this method
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6ꢀmethoxyꢀ4ꢀarylꢀ2ꢀquinolones were obtained in lowꢀtoꢀmoderate yields when using
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pꢀsubstituted phenylboronates. Since this inefficiency can be ascribed to the diminished
electrophilicity of the propiolate due to the electronꢀdonating effect of the methoxy
substituent, the synthesis of polymethoxylated analogs using this method seems to be a
formidable challenge. Herein, we report the successful synthesis of polymethoxylated
4ꢀarylꢀ2ꢀquinolones and the diversityꢀoriented transformations of the product (Figure 2).
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RESULTS AND DISCUSSION
Syntheses of amyloid β fibrogenesis inhibitor 1 and natural product 6. First,
the oneꢀpot Cuꢀcatalyzed hydroarylation/lactam formation was investigated using
polymethoxylated (oꢀaminophenyl)propiolates 2a and 2b as the substrates. Propiolates 2a
and 2b were prepared following the previously reported method (Scheme 1). Although
harsh reaction conditions were required, the Sonogashira coupling of the corresponding
polymethoxylated iodobenzenes with trimethylacetylene afforded the required silylalkyne
precursors. The subsequent Kondo’s carboxylation of the silylalkynes efficiently
proceeded in DMF at room temperature to afford the desired propiolates 2a and 2b in high
yields.8
Scheme 1. Preparation of polymethoxylated (oꢀaminophenyl)propiolates 2a and 2b.
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According to our previously established procedure,7 the hydroarylation of 2a with 3
equiv of pꢀfluorophenylboronate 3a was carried out in the presence of Cu(OAc)2 in
MeOH at 28 °C for 12 h (Scheme 2). To ensure high conversion, the Cu catalyst loading
was increased to 10 mol %. Then, the Boc group was removed by adding TfOH (3 equiv)
to the same pot and stirring the reaction mixture at 65 °C for 2 h. The desired
benzylꢀprotected 2ꢀquinolone 4aa was obtained in 59% yield. Gratifyingly, the yield
further increased to 72% when the loading of 2a was increased to 5 equiv.
Scheme 2. Synthesis of 4ꢀarylꢀ2ꢀquinolone 4aa from 2a and 3a.
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Accordingly, 2a was exemplified to be a good substrate for the 4ꢀarylꢀ2ꢀquinolone
synthesis as opposed to our initial anticipation that the multiple substitution with
electronꢀdonating methoxy groups renders it much less reactive than previously reported
(2ꢀaminoꢀ5ꢀmethoxyphenyl)propiolate 2c.7 To compare the reactivity of 2a and 2c, the
reaction of 2a with pꢀanisylboronate 3b was performed under the exactly same conditions
previously reported (Scheme 3).7 As a result, 4ab was obtained in 63% yield, which is
significantly higher than that for the reaction of 2c with 3b (39%).
Scheme 3.
Hydroarylation/cyclization of propiolates 2a and 2c (ref. 7) with
pꢀanisylboronate 3b.
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Then, 4aa was debenzylated to obtain 1 under radical conditions as per a previous
report (Scheme 4),9 because we previously found that hydrogeneolysis using Pd/C was
totally incompetent for Nꢀbenzylꢀ4ꢀ(pꢀchlorophenyl)ꢀ2(1H)ꢀquinolone.7 Thus, 4aa was
treated with Nꢀbromosuccinimide (NBS, 1.5 equiv) in the presence of
azobisisobutyronitrile (AIBN, 0.2 equiv) in chlorobenzene under reflux for 10 h, and the
reaction mixture was then stirred at room temperature for another 2 h after adding
H2O/EtOH. However, C3ꢀbromination product 5 was unexpectedly obtained in 68% yield.
The formation of 5 can be attributed to the electrophilic dehydrobromination at the C3
position (vide infra). Next, the standard hydrogenolysis conditions (Pd/C, 1 atm H2, EtOH,
rt) were applied to 4aa. The debenzylation proceeded for 20 h, affording the desired
product 1 in 97% yield.
Scheme 4. Debenzylation of 4ꢀarylꢀ2ꢀquinolone 4aa.
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Having accomplished the synthesis of 1, the synthesis of naturally occurring
alkaloid 6 was attempted to evaluate if this method has general applicability. Alkaloid 6
has a characteristic substitution pattern: naturally occurring 2ꢀquinolones generally
contain oxygen functional groups at the C4 position, whereas 6 has a pꢀanisyl group at
this position.1a,10 The Cuꢀcatalyzed hydroarylation of dimethoxylated substrate 2b with
pꢀanisylboronate 3b (3.0 equiv) followed by the acidic removal of the Boc group afforded
4bb in 86% yield (Scheme 5). Notably, 3.0 equiv of 3b was enough to obtain a high yield
of 4bb, in contrast to the reaction of 2a with 3a. Because the debenzylation of 4bb under
hydrogenolysis conditions failed in EtOH, the debenzylation was conducted in a mixed
solvent of AcOH/EtOH (1:1 v/v) for 12 h, affording the desired product 6 in 97% yield.
Scheme 5. Synthesis of alkaloid 6 from 2b and 3b.
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As shown above, polymethoxylated phenylpropiolates 2a and 2b exhibited higher
reactivity compared to monomethoxy analog 2c, although the increased number of
electronꢀdonating methoxy substituents decreases the electrophilicity of 2a and 2b. In fact,
the density functional theory calculations (see Supporting Information for details) showed
that the LUMO level of 2a (–0.07052 eV) and 2b (–0.07021 eV) is higher than that of 2c
(–0.07814 eV). Therefore, the reason for the higher reactivity of 2a and 2b should be
considered. Previously, we found that a propargylic methoxy group increases the
reactivity of the propiolate substrate, resulting in the formation of multiple insertion
products.11 In this case, the chelate formation of vinylcopper intermediates with the
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additional propiolate substrate was proposed as a cause. In a similar manner, the methoxy
substituents at the 6 position of the aniline terminal of 2a and 2b possibly direct
arylcopper species in close proximity to the alkyne, facilitating the carbocupuration
(IntꢀA → IntꢀB in Scheme 6). Because the decrease in the electrophilicity owing to
additional methoxy substituents was significantly compensated by this directing effect.
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Scheme 6. Plausible methoxyꢀgroupꢀdirected carbocupration of 2a and 2b.
Divergent synthesis of the analogs of 1. The method was extended to the
synthesis of polymethoxylated 4ꢀarylꢀ2ꢀquinolones, closely relevant to 1. To this end, the
oneꢀpot Cuꢀcatalyzed hydroarylation/lactam formation was investigated using 2a with
various arylboronates (Scheme 7). Consequently, the desired products 4ab–4ak,
possessing electronꢀdonating and electronꢀwithdrawing groups were obtained in 25–77%
yields. Substitutions at the para and metha positions were allowed, although
oꢀfluorophenylboronate did not afford the corresponding product. 3,4ꢀ or
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3,5ꢀDisubstituted phenylboronates could be used without significant lowering product
yields. However, the reaction using pꢀ(methoxycarbonyl)phenylboronate 3d and
3,4,5ꢀtrifluorophenylboronate 3i resulted in a low yield of 4ad and 4ai. It is reasoned that
these electronꢀdefficient arylboronates decrease efficiency of the reaction with less
electrophilic propiolate 2a.
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Scheme 7. Synthesis of 4ꢀarylꢀ2ꢀquinolones 4ab–4ak.
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As described above, the debenzylation of 4aa was attempted under the radical
conditions, but the unexpected C3ꢀbromination product 5 was obtained instead of 1
(Scheme 4). Because Csp2–X bonds can be used for further derivatization via
transitionꢀmetalꢀcatalyzed crossꢀcoupling reactions, the dehydrohalogenation of 4aa was
investigated in detail (Scheme 8). It was previously reported that dehydrobromination and
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dehydrochlorination occurred at the C3 position of 2ꢀquinolones under radical
conditions.12 On the other hand, it was also reported that the dehydrobromination of
4ꢀphenylꢀ1ꢀmethylꢀ2ꢀquinolone occurred at both the C3 and C6 positions in the absence
of radical initiator AIBN.13 In our hand, when 4aa was treated with NBS (1.5 equiv) in the
absence of AIBN, 5 was obtained as a single product with an improved yield of 90%.
Because iodides are generally more reactive than the corresponding bromides in
transitionꢀmetalꢀcatalyzed crossꢀcoupling reactions, the dehydroiodination of 4aa was
attempted using Nꢀiodosuccinimide (NIS) under similar conditions. However, the
corresponding iodination product was not obtained. This is because of the lower
electrophilicity of NIS than NBS. Sutherland and coꢀworkers recently reported the
iodination of arenes with NIS in the presence of a catalytic amount of AgNTf2. Thus, this
catalytic method was applied to our 2ꢀquinolone system. In the presence of 7.5 mol %
AgNTf2,14 4aa was treated with 1.1 equiv of NIS in dichloromethane at 35 °C for 24 h,
exclusively providing C3ꢀiodination product 7 in 95% yield.
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Scheme 8. Dehydrobromination and dehydroiodination of 4aa.
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Further derivatizations of iodinated 2ꢀquinolone 7 were conducted as summarized in
Scheme 9. The Suzuki–Miyaura coupling15 with pꢀanisylboronic acid and Mizoroki–Heck
reaction16 with ethyl acrylate were performed using the Herrmann’s palladacycle catalyst
(8),17 affording 3ꢀarylation product 9 and 3ꢀolefination product 10 in 88% yields,
respectively. On the other hand, 7 was treated with CuCN (3 equiv) or Cu(C≡CPh) (3
equiv) in pyridine at reflux for 3 h, affording 3ꢀcyanoꢀ2ꢀquinolone 11 and
3ꢀalkynylꢀ2ꢀquinolone 12 in high yields.18 Moreover, Cuꢀmediated trifluoromethylation19
was conducted using methyl difluoro(fluorosulfonyl)acetate (MFSDA), affording
3ꢀtrifluoromethylꢀ2ꢀquinolone 13 in 86% yield. These highꢀyield syntheses of the
C3ꢀfuctionalized polymethoxylated derivatives of 1 well demonstrated the versatility of
our diversification strategy.
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Scheme 9. Coupling reactions of 3ꢀiodoꢀ2ꢀquinolone 7.
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Finally, the selective Nꢀbenzylation of 1 was investigated to synthesize the
corresponding derivative possessing a polyoxygenated Nꢀbenzyl group (Scheme 10). It is
known that the benzylation of 2ꢀquinolones produces the corresponding Nꢀbenzylation
products along with Oꢀbenzylation products with different selectivity depending on the
reaction conditions.20 In fact, when 1 was treated with 1.1 equivs of NaH and
pꢀmethoxybenzyl chloride (PMBCl) in DMF at room temperature for 6 h, the desired
2ꢀquinolone 14a and quinoline byproduct 15a were obtained in 53% and 28% yields,
respectively. Thus, a method that selectively affords Nꢀbenzylation products was used.21
The reaction of 1 with PMBCl (1.1 equiv) was performed in the presence of Cs2CO3 (2.0
equiv) in dioxane at room temperature. However, the reaction was sluggish; therefore, the
reaction mixture was refluxed for 12 h. Thus, 14a was selectively obtained in 80% yield
along with reduced amounts of 15a (11%). Similarly, the reaction of 1 with
2ꢀ(bromomethyl)ꢀ1,4ꢀdimethoxybenzene (1.1 equiv) was performed at a lower
temperature of 60 °C for 6 h, affording Nꢀbenzylation product 14b in 84% yield (Scheme
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11).
The
reactions
using
5ꢀ(bromomethyl)benzo[d][1,3]dioxole
and
5ꢀ(bromomethyl)ꢀ1,2,3ꢀtrimethoxybenzene also afforded Nꢀbenzylation products 14c and
14d in 87% and 79% yields, respectively. In these cases, the formation of the
corresponding Oꢀbenzylation byꢀproducts was effectively suppressed (<10%).
Scheme 10. Selective benzylation of 1 with PMBCl
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Scheme 11. Synthesis of 14b–d via benzylation of 1.
CONCLUSIONS
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The divergent synthesis of polymethoxylated 4ꢀarylꢀ2ꢀquinolones was successfully
achieved. First, amyloid β fibrogenesis inhibitor 1 and natural alkaloid 6 with
polymethoxylated 2ꢀquinolone cores were efficiently synthesized by oneꢀpot Cuꢀcatalyzed
hydroarylation/lactam formation and subsequent debenzylation. The oneꢀpot
hydroarylation/lactam formation was carried out using various arylboronates, affording
the derivatives of Nꢀbenzylated 1 and 6, possessing different aryl groups at the C4
position.
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Then, the diversification of 1 afforded diverse derivatives. The Agꢀcatalyzed
dehydroiodination of Nꢀbenzylated 1 produced the C3ꢀiodination product, and subsequent
palladiumꢀcatalyzed crossꢀcoupling reactions such as Suzuki–Miyaura coupling and
Mizoroki–Heck
reaction,
and
Cuꢀmediated
cyanation,
alkynylation,
and
trifluoromethylation reactions afforded the corresponding C3ꢀfunctionalized derivatives of
1. The selective Nꢀbenzylation of 1 also afforded several analogs of 1, possessing
polyoxygenated Nꢀbenzyl groups in high yields.
EXPERIMENTAL SECTION
General. Column chromatography was performed on silica gel (Cica silica gel
1
60N) with solvents specified below. H, 13C, and 19F NMR spectra were obtained for
1
samples in CDCl3 solutions at 25 °C. H NMR chemical shifts are reported in terms of
chemical shift (δ, ppm) relative to the singlet at 7.26 ppm for chloroform. 19F NMR spectra
are reported in terms of chemical shift (δ, ppm) relative to the singlet at δ –63.7 ppm for
α,α,αꢀtrifluorotoluene as an external standard. Splitting patterns are designated as follows:
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s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; sept, septet; m,
multiplet. Coupling constants are reported in Hz. 13C NMR spectra were fully decoupled
and are reported in terms of chemical shift (δ, ppm) relative to the triplet at δ 77.0 ppm for
CDCl3. High resolution mass spectra (HRMS) were obtained on a ESIꢀTOF mass
spectrometer. Dry solvents were purchased and used as received. Microwaveꢀheating
experiments were carried out with a singleꢀmode microwave reactor (CEM Discover
LabꢀMate). Closed reaction vessels were used, and the temperature was monitored by an
online IR detector.
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Preparation of (oꢀAminophenyl)propiolates 2
Representative procedure for protection of anilines – Synthesis of tertꢀbutyl
3,4,5ꢀtrimethoxyphenylcarbamate:22 In a flask, a solution of 3,4,5ꢀtrimethoxyaniline
(1.73 g, 9.5 mmol) in diꢀtꢀbutyl dicarbonate (3.5 mL, 3.31g, 15.2 mmol) was heated at
90 °C for 3 h. After cooled to room temperature, the reaction mixture was concentrated in
vacuo. The crude product was purified by flash column chromatography on silica gel
(hexane/EtOAc = 4:1~2:1) to afford tertꢀbutyl 3,4,5ꢀtrimethoxyphenylcarbamate (2.44 g,
91%) as an white solid (mp 149.4ꢀ153.2 °C, lit22 mp 151–153 °C); 1H NMR (400 MHz,
CDCl3, 25 °C) δ 6.65 (s, 2 H), 6.40 (br s, 1 H), 3.85 (s, 6 H), 3.80 (s, 3 H) 1.51 (s, 9 H);
13C NMR (100 MHz, CDCl3, 25 °C) δ 153.4, 152.7, 134.5, 133.7, 96.1, 80.5, 61.0, 56.1,
28.3.
tertꢀButyl 3,5ꢀdimethoxyphenylcarbamate:23 The title compound was similarly
prepared from 3,5ꢀdimethoxyꢀ2ꢀaniline; 2.48 g, 98%; white solid (mp 81.2–82.3 °C, lit23
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mp 75–76 °C); 1H NMR (400 MHz, CDCl3, 25 °C) δ 6.59 (d, J = 2.0 Hz, 2 H), 6.43 (br s,
1 H), 6.16 (t, J = 2.0 Hz, 1 H), 3.77 (s, 6 H), 1.51 (s, 9 H); 13C NMR (100 MHz, CDCl3,
25 °C) δ 161.1, 152.5, 140.2, 96.6, 95.5, 80.5, 55.3, 28.3.
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Synthesis of tertꢀbutyl 2ꢀiodoꢀ3,4,5ꢀtrimethoxyphenylcarbamate:
compound was prepared according to the report.24
The title
To a solution of tertꢀbutyl
3,4,5ꢀtrimethoxyphenylcarbamate (1.04 g, 3.68 mmol) in chloroform (110 mL) was added
iodine (1.03 g, 11.0 mmol) and grinded silver trifluoroacetate (2.44 g, 0.19 mmol) at room
temperature. The reaction mixture was stirred at room temperature for 8 h. Insoluble
materials were filtered off and rinsed with chloroform (10 mL), and the filtrate was
concentrated in vacuo. The obtained crude material was purified by flash column
chromatography on silica gel (hexane/EtOAc
=
10:1) to afford tertꢀbutyl
2ꢀiodoꢀ3,4,5ꢀtrimethoxyphenylcarbamate (1.12 g, 80%) as a white solid (mp 135.6–136.4
˚C): 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.66 (s, 1 H), 6.89 (s, 1 H), 3.88 (s, 3 H), 3.86
(s, 3 H), 3.81 (s, 3 H), 1.52 (s, 9 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 154.1, 152.8,
152.7, 137.7, 135.2, 99.8, 80.9, 76.2, 61.0, 60.8, 56.1, 28.3; IR (neat) 3392 (N–H), 1730
(C=O) cm–1; HRMS (ESI) m/z calcd for C14H20INO5•Na 432.0284, found 432.0282
[M+Na]+.
Synthesis of tertꢀbutyl 2ꢀiodoꢀ3,5ꢀdimethoxyphenylcarbamate: To a solution of
tertꢀbutyl 3,5ꢀdimethoxyphenylcarbamate (126.4 mg, 0.50 mmol) in dichloromethane (1.0
mL) was added Nꢀiodosuccinimide (123.4 g, 0.55 mmol) at room temperature. The reaction
mixture was stirred at room temperature for 3 h. Then, the mixture was washed with H2O (2
× 10 mL), brine (10 mL), and dried over Na2SO4. After concentration in vacuo, the
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obtained crude material was purified by flash column chromatography on silica gel
(hexane/EtOAc = 100:1) to afford tertꢀbutyl 2ꢀiodoꢀ3,5ꢀdimethoxyphenylcarbamate (81.6
mg, 43%) as a white solid (mp 129.0–129.7 °C): 1H NMR (400 MHz, CDCl3, 25 °C) δ
7.52 (d, J = 2.4 Hz, 1 H), 7.10 (br s, 1 H), 6.18 (d, J = 2.4 Hz, 1 H), 3.842 (s, 3 H), 3.835 (s,
3 H), 1.53 (s, 9 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 161.6, 158.5, 152.5, 140.4,
96.5, 94.2, 80.9, 69.5, 56.3, 55.6, 28.3; IR (neat) 2974 (N–H), 1700 (C=O) cm–1;
HRMS (ESI) m/z calcd for C13H18INO4•Na 402.0178, found 402.0177 [M+Na]+.
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Representative procedure for benzylation of oꢀiodoaniline – Synthesis of
tertꢀbutyl benzyl(2ꢀiodoꢀ3,4,5ꢀtrimethoxyphenyl)carbamate: To a solution of the
tertꢀbutyl 2ꢀiodoꢀ3,4,5ꢀtrimethoxyphenylcarbamate (1.09 g, 2.66 mmol) in DMF (13.3 mL)
was added sodium hydride (60% oil, 0.21 g, 5.33 mmol) at 0 °C. The reaction mixture was
stirred at room temperature for 1 h. To the resultant mixture was added benzyl bromide
(0.38 mL, 3.20 mmol). The reaction mixture was stirred at room temperature for 1 h. The
reaction was quenched with sat. NH4Cl (10 mL), and the mixture was extracted with AcOEt
(3 × 30 mL). The combined organic layer was washed with water (2 × 20 mL), brine (10
mL), and dried over MgSO4. After concentration in vacuo, the crude product was purified
by flash column chromatography on silica gel (hexane/EtOAc = 10:1) to afford tertꢀbutyl
benzyl(2ꢀiodoꢀ3,4,5ꢀtrimethoxyphenyl)carbamate (1.28 g, 96%) as a white solid (mp 85.4–
86.0 °C): a mixture of two rotamers; 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.55–7.00
(major+minor) (br m, 5 H), 6.21 (minor)/6.03 (major) (br s, 1 H), 5.33 (major)/5.22 (minor)
(br d, J = 15 Hz, 1 H), 4.01 (minor)/3.97 (minor) (br d, J = 15 Hz, 1 H), 3.88
(minor)/3.85(major) (br s, 3 H), 3.88 (major)/3.83(minor) (br s, 3 H), 3.54 (minor)/3.50
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(major) (br s, 3 H), 1.57 (minor)/1.39 (major) (br s, 9 H); 13C NMR (100 MHz, CDCl3,
25 °C) δ 154.1 (major)/153.8 (minor), 153.9 (minor)/153.42 (major), 153.35 (minor)/153.0
(major), 141.3 (minor)/141.1 (major), 139.8 (minor)/139.5 (major), 138.0 (minor)/137.9
(major), 129.1 (major)/128.5 (minor), 128.2 (major)/127.3 (minor), 110.3 (minor)/110.1
(major), 87.9 (major+minor), 80.9 (minor)/80.2 (major), 60.9 (minor)/60.8 (major), 55.7
(major+minor), 53.8 (minor)/52.4 (major), 28.4 (minor)/28.2 (major); IR (neat) 1702
(C=O) cm–1; HRMS (ESI) m/z calcd for C21H26INO5•Na 522.0753, found 522.0744
[M+Na]+.
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tertꢀButyl benzyl(2ꢀiodoꢀ3,5ꢀdimethoxyphenyl)carbamate: The title compound
was prepared from tertꢀbutyl 2ꢀiodoꢀ3,5ꢀdimethoxyphenylcarbamate using the above
procedure; 1.70 g, 94%; white solid (mp 98.8–99.4 °C): a mixture of two rotamers; 1H
NMR (400 MHz, CDCl3, 25 °C) δ 7.30–7.18 (major+minor) (br m, 5 H), 6.31
(minor+major) (br s, 1 H), 6.09 (minor)/5.90 (major) (br s, 1 H), 5.31 (minor)/4.00 (major)
(d, J = 15 Hz, 1 H), 5.19 (minor)/4.04 (major) (d, J = 15 Hz, 1 H), 3.85 (major+minor) (br s,
3 H), 3.56 (minor)/3.54 (major) (br s, 3 H), 1.55 (minor)/1.38 (major) (br s, 9 H); 13C
NMR (100 MHz, CDCl3, 25 °C) δ 161.0 (minor)/160.5 (major), 159.8 (minor)/159.4
(major), 154.2 (major)/153.9 (minor), 146.0 (minor)/145.7 (major), 138.2 (minor)/138.0
(major), 129.2 (major)/128.5 (minor), 128.2 (major)/127.3 (minor), 107.4 (major+minor),
98.4 (minor)/97.8 (major), 81.6 (minor)/81.4 (major), 80.9 (minor)/80.3 (major), 56.5
(major+minor), 55.4 (major+minor), 53.9 (minor)/52.5 (major), 28.5 (minor)/28.3 (major);
IR (neat) 1700 (C=O) cm–1; HRMS (ESI) m/z calcd for C20H24INO4•Na 492.0648, found
492.0641 [M+Na]+.
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Representative procedure for Sonogashira coupling of oꢀiodoaniline – Synthesis
of tertꢀbutyl benzyl(3,4,5ꢀtrimethoxyꢀ2ꢀ((trimethylsilyl)ethynyl)phenyl)carbamate: In
a shield tube, to a solution of tertꢀbutyl benzyl(2ꢀiodoꢀ3,4,5ꢀtrimethoxyphenyl)carbamate
(499.1 mg, 1.0 mmol) and diisopropylamine (1.52 g, 15.0 mmol) in DMF (0.5 mL) was
added PdCl2(PPh3)2 (21.1 mg, 0.03 mmol), CuI (5.6 mg, 0.03 mmol) and
trimethylsilylacetylene (207.0 ꢁL, 1.50 mmol) at room temperature. The shield tube was
irradiated with a microwave reactor (300 W output, 250 PSI) at 120 °C for 15 min. After
adding sat. NH4Cl (10 mL), the reaction mixture was extracted with AcOEt (3 × 20 mL).
The combined organic layer was washed with water (20 mL), brine (10 mL), and dried over
MgSO4. After concentration in vacuo, the crude product was purified by flash column
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chromatography on silica gel (hexane/EtOAc
=
10:1) to afford tertꢀbutyl
benzyl(3,4,5ꢀtrimethoxyꢀ2ꢀ((trimethylsilyl)ethynyl)phenyl)carbamate (0.36 g, 77%) as a
yellow oil; a mixture of two rotamers; 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.32–7.18
(major+minor) (br m, 5 H), 6.21 (minor)/6.02 (major) (br s, 1 H), 5.23 (minor)/5.20 (major)
(br s, 1 H), 4.26 (major)/4.23 (minor) (br s, 1 H), 3.98 (minor)/3.95 (major) (br s, 3 H), 3.80
(major+minor) (br s, 3 H), 3.63 (minor)/3.58 (major) (br s, 3 H), 1.51 (minor)/1.37 (major)
(br s, 9 H), 0.25 (major+minor) (br s, 9 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 155.4
(minor)/155.0 (major), 154.7 (major)/154.5 (minor), 153.5 (minor)/153.1 (major), 141.0
(minor)/140.8 (major), 140.6 (major/minor), 138.5 (minor)/138.3 (major), 128.9
(major/minor), 128.1 (major/minor), 127.1 (major/minor), 110.0 (minor+major), 109.3
(minor)/108.9 (major), 101.8 (major/minor), 97.7(major/minor), 80.6 (minor)/79.8 (major),
61.1 (major+minor), 55.8 (major+minor), 53.9 (minor)/52.6 (major), 28.4 (minor)/28.2
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(major), –0.1 (major+minor); IR (neat) 2154 (C≡C), 1704 (C=O), 1250 (Si–CH3), 843
(Si–CH3) cm–1; HRMS (ESI) m/z calcd for C26H35NO5Si•Na 492.2182, found 492.2196
[M+Na]+.
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tertꢀButyl
benzyl(3,5ꢀdimethoxyꢀ2ꢀ((trimethylsilyl)ethynyl)phenyl)carbamate:
compound was prepared from tertꢀbutyl
The
title
benzyl(2ꢀiodoꢀ3,5ꢀdimethoxyphenyl)carbamate using the above procedure; 0.51 g, 76%;
yellow oil; a mixture of two rotamers; 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.32–7.17
(major+minor) (br m, 5 H), 6.29 (major+minor) (br s, 1 H), 6.12 (minor)/5.89 (major) (br s,
1 H), 5.29 (minor)/5.25 (major) (br s, 1 H), 4.24 (major)/4.20 (minor) (br s, 1 H), 3.84
(major+minor) (s, 3 H), 3.63 (minor)/3.59 (major) (br s, 3 H), 1.50 (minor)/1.37 (major) (br
s, 9 H), 0.26 (major+minor) (s, 9 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 162.1
(minor)/161.5 (major), 160.4 (minor)/160.0 (major), 154.6 (major)/154.2 (minor), 146.8
(major+minor), 138.5 (minor)/138.2 (major), 128.7 (minor)/128.1 (major), 127.0
(major/minor), 106.6 (major+minor), 104.6 (minor)/104.4 (major), 101.7 (major+minor),
98.0 (major+minor), 97.5 (minor)/97.0 (major), 80.4 (minor)/79.7 (major), 55.9
(major+minor), 55.2 (major+minor), 53.7 (minor)/52.4 (major), 28.3 (minor)/28.2 (major),
0.0 (major+minor); IR (neat) 2153 (C≡C), 1703 (C=O), 1250 (Si–CH3), 842 (Si–CH3)
cm–1; HRMS (ESI) m/z calcd for C25H33NO4Si•Na 462.2077, found 462.2089 [M+Na]+.
Representative procedure for carboxylation of silylalkyne – Synthesis of methyl
3ꢀ(6ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ2,3,4ꢀtrimethoxyphenyl)propiolate (2a): In
a flask, cesium fluoride (1.51 g, 9.9 mmol) was heated under vacuum at 120 °C for 1 h. The
flask was filled with CO2 and then with dry DMF (2.5 mL). To the resultant suspension was
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added
dropwise
a
solution
of
tertꢀbutyl
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benzyl(3,4,5ꢀtrimethoxyꢀ2ꢀ((trimethylsilyl)ethynyl)phenyl)carbamate (1.88 g, 5.0 mmol) in
dry DMF (10 mL) at room temperature. The reaction mixture was stirred at room
temperature for 6 h. After addition of methyl iodide (0.37 mL, 5.9 mmol), the stirring was
continued at room temperature for another 1 h. The reaction was quenched with sat. NH4Cl
(20 mL) and the whole mixture was extracted with AcOEt (3 × 50 mL). The combined
organic layer was washed with water (2 × 30 mL), brine (10 mL), and dried over MgSO4.
After concentration in vacuo, the crude material was purified by flash column
chromatography on silica gel (hexane/EtOAc = 15:1) to yield propiolate 2a (1.56 g, 86%)
as a white solid (mp 82.6–84.8 °C): a mixture of two rotamers; 1H NMR (400 MHz,
CDCl3, 25 °C) δ 7.32–7.18 (major+minor) (br m, 5 H), 6.27 (minor)/6.12 (major) (br s, 1
H), 5.40–4.20 (major+minor) (br m, 2 H), 3.99 (minor)/3.96 (major) (br s, 3 H), 3.82
(minor)/3.81 (major) (br s, 6 H), 3.65 (br s, 3 H), 1.53 (minor)/1.39 (major) (br s, 9 H);
13C NMR (100 MHz, CDCl3, 25 °C) δ 156.2 (major+minor), 155.7 (major+minor), 155.2
(major+minor), 154.3 (major+minor), 142.5 (major+minor) 141.7 (major+minor), 140.7
(major+minor), 138.1 (major+minor), 137.8 (major+minor), 128.9 (minor)/128.3 (major),
127.4 (major+minor), 108.8 (minor)/ 108.4 (major), 106.9 (major+minor), 87.0
(major/minor), 81.3 (minor)/80.6 (major), 61.7 (major+minor), 61.1 (major+minor), 55.9
(major+minor), 54.4 (major+minor), 53.2 (minor)/52.5 (major), 28.2 (major+minor); IR
(neat) 2217 (C≡C), 1709 (C=O) cm–1; HRMS (ESI) m/z calcd for C25H29NO7•Na
478.1842, found 478.1828 [M+Na]+.
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title
compound
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tertꢀbutyl
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benzyl(3,5ꢀdimethoxyꢀ2ꢀ((trimethylsilyl)ethynyl)phenyl)carbamate using the above
procedure; 226.1 mg, 88%; white solid (mp 99.6–100.8 °C); a mixture of two rotamers;
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.30–7.17 (br, 5 H), 6.31 (minor+major) (br s, 1 H),
6.18 (minor)/6.04 (major) (br s, 1 H), 5.22–4.38 (major+minor) (br m, 2 H), 3.84
(major+minor) (s, 3 H), 3.80 (major+minor) (s, 3 H), 3.67 (major+minor) (s, 3 H), 1.50
(minor)/1.40 (major) (br s, 9 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 163.3
(major+minor), 162.3 (major+minor), 154.6 (major+minor), 154.2 (major+minor), 148.6
(minor)/147.9 (major), 138.1 (minor)/137.7 (major), 128.8 (minor)/128.2 (major), 127.3
(major+minor), 106.3 (major+minor), 101.5 (major+minor), 97.3 (minor)/ 96.8 (major),
87.4 (major/minor), 81.3 (major+minor), 81.2 (minor)/80.6 (major), 56.1 (major+minor),
55.5 (major+minor), 54.3 (minor)/53.2 (major), 52.5 (major+minor), 28.2 (major+minor);
IR (neat) 2214 (C≡C), 1706 (C=O) cm–1; HRMS (ESI) m/z calcd for C24H27NO6•Na
448.1736, found 448.1723 [M+Na]+.
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The H NMR spectra for 2a and 2b were also obtained for samples in tolueneꢀd8 at
60 °C: 2a: 1H NMR (400 MHz, tolueneꢀd8, 60 °C) δ 7.23 (d, J = 7.2 Hz, 2 H), 7.07–6.95
(m, 3 H), 6.12 (s, 1 H), 4.78 (br s, 2 H), 3.78 (s, 3 H), 3.56 (s, 3 H), 3.38 (s, 3 H), 3.08 (s, 3
H), 1.46 (s, 9 H); 2b: 1H NMR (400 MHz, tolueneꢀd8, 60 °C) δ 7.27 (d, J = 7.2 Hz, 2 H),
7.08–6.92 (m, 3 H), 6.10 (br s, 1 H), 5.98 (s, 1 H), 4.85 (br s, 2 H), 3.38 (s, 3 H), 3.16 (s, 3
H), 3.10 (s, 3 H), 1.45 (s, 9 H).
Synthesis of 4ꢀArylꢀ2ꢀquinolones
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Representative procedure for oneꢀpot hydroarylation/cyclization – Synthesis of
1ꢀbenzylꢀ5,7ꢀdimethoxyꢀ4ꢀ(4ꢀmethoxyphenyl)quinolinꢀ2(1H)ꢀone (4bb): To a solution
of propiolate 2b (127.8 mg, 0.30 mmol) in dry methanol (0.6 mL) was added
pꢀmethoxyphenylboronate 3b (198.8 mg, 0.90 mmol) and Cu(OAc)2 (5.44 mg, 0.03 mmol)
at room temperature under an argon atmosphere. The mixture was degassed at –78 °C and
stirred at 28 °C for 12 h. After addition of trifluoromethanesulfonic acid (79.0 ꢁL, 0.90
mmol), the stirring was continued at 65 ˚C for another 2 h. The reaction was quenched with
10% NaOH (10 mL) and the whole mixture was extracted with AcOEt (3 × 20 mL). The
combined organic layer was washed with brine (10 mL) and dried over MgSO4. After
concentration in vacuo, the crude material was purified by flash column chromatography on
silica gel (hexane/EtOAc = 5:1) to afford 2ꢀquinolone 4bb (103.9 mg, 86%) as a white
solid (mp 142.3–144.2 °C): 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.35–7.23 (m, 5 H),
7.21 (m, 2 H), 6.90 (m, 2 H), 6.42 (s, 1 H), 6.41 (d, J = 2.4 Hz, 1 H), 6.17 (d, J = 2.4 Hz, 1
H), 5.57 (br s, 2 H), 3.87 (s, 3 H), 3.70 (s, 3 H), 3.42 (s, 3 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 162.3, 162.1, 159.0, 158.7, 150.3, 142.7, 136.7, 134.5, 128.8, 128.5, 127.2,
126.6, 119.2, 112.5, 105.6, 93.8, 92.3, 55.3, 55.2, 46.7; IR (neat) 1648 (C=O), 1606
(C=C) cm–1; HRMS (ESI) m/z calcd for C25H23NO4•Na 424.1525, found 424.1513
[M+Na]+.
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4ꢀArylꢀ2ꢀquinolones 4aa–4ak were also synthesized according to the above
procedure, except for using 5 equiv of arylboronates.
1ꢀBenzylꢀ4ꢀ(4ꢀfluorophenyl)ꢀ5,6,7ꢀtrimethoxyquinolinꢀ2(1H)ꢀone (4aa):
90.1
mg, 72%; white solid (mp 147.5–150.9 °C); 1H NMR (400 MHz, CDCl3, 25 °C) δ
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7.38–7.26 (m, 7 H), 7.08 (tt, J = 8.6, 2.4 Hz, 2 H), 6.59 (s, 1 H), 6.46 (s, 1 H), 5.58 (br s, 2
H), 3.75 (s, 3 H), 3.73 (s, 3 H), 3.24 (s, 3 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 162.0
(d, J = 244.1 Hz), 161.7, 155.8, 151.3, 149.1, 138.0, 137.3, 137.0 (d, J = 3.8 Hz), 136.5,
129.1 (d, J = 7.6 Hz), 129.0, 127.4, 126.7, 120.7, 114.1 (d, J = 21.9 Hz), 109.2, 94.6, 60.9,
60.7, 55.7, 46.7; 19F NMR (376 MHz, CDCl3, 25 °C) δ –115.18; IR (neat) 1653 (C=O)
cm–1; HRMS (ESI) m/z calcd for C25H22FNO4•Na 442.1431, found 442.1421 [M+Na]+.
1ꢀBenzylꢀ5,6,7ꢀtrimethoxyꢀ4ꢀ(4ꢀmethoxyphenyl)quinolinꢀ2(1H)ꢀone (4ab): 99.7
mg, 77%; white solid (mp 117.0–119.5 °C); 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.37–
7.24 (m, 7 H), 6.93 (d, J = 8.8 Hz, 2 H), 6.59 (s, 1 H), 6.47 (s, 1 H), 5.58 (br s, 2 H), 3.87 (s,
3 H), 3.76 (s, 3 H), 3.73 (s, 3 H), 3.24 (s, 3 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ
161.9, 158.8, 155.6, 151.6, 150.0, 138.1, 137.4, 136.7, 133.5, 128.9, 128.8, 127.4, 126.7,
120.6, 112.6, 109.5, 94.6, 61.0, 60.9, 55.7, 55.3, 46.7; IR (neat) 1652 (C=O) cm–1;
HRMS (ESI) m/z calcd for C26H25NO5•Na 454.1630, found 454.1631 [M+Na]+.
1ꢀBenzylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ5,6,7ꢀtrimethoxyquinolinꢀ2(1H)ꢀone (4ac): 85.0 mg,
65%; white solid (mp 103.5–106.4 °C); 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.40–7.24
(m, 9 H), 6.59 (s, 1 H), 6.44 (s, 1 H), 5.58 (br s, 2 H), 3.75 (s, 3 H), 3.73 (s, 3 H), 3.26 (s, 3
H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 161.7, 155.9, 151.3, 149.0, 139.7, 138.0, 137.4,
136.5, 133.0, 128.9, 128.8, 127.4, 126.7, 120.6, 109.0, 94.6, 60.9, 60.7, 55.8, 46.7; IR
(neat) 1653 (C=O) cm–1; HRMS (ESI) m/z calcd for C25H22ClNO4•Na 458.1135, found
458.1133 [M+Na]+.
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1ꢀBenzylꢀ4ꢀ[4ꢀ(methoxycarbonyl)phenyl]ꢀ5,6,7ꢀtrimethoxyquinolinꢀ2(1H)ꢀone
(4ad): 35.5 mg, 26%; white solid (mp 152.5–154.6 °C); 1H NMR (400 MHz, CDCl3,
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